Human postnatal dental stem cells such as dental pulp stem cells (DPSCs) and stem cells from root apical papilla (SCAPs) are unique precursor populations isolated from dental tissues based on the primary characteristics of bone marrow mesenchymal stem cells (MSCs). Like bone marrow MSCs, dental stem cells are self-renewing, multipotent, and clonogenic. They can be induced to differentiate into odontoblast- or osteoblast-like cells and form mineralized nodules in vitro. When implanted into immunodeficient mice, dental stem cells can form dentin- or cementum-like mineralized tissues or related craniofacial structures. Hence dental stem cells may present promising prospects for tooth regeneration and tissue repair. However, currently, the molecular regulation of their differentiation is poorly understood. Histone demethylases are newly-identified enzymes for removing histone methyl markers associated with gene activation or silencing. While they have been implicated in developmental processes and human diseases, it is largely unknown whether and how histone demethylases play a critical role in regulating dental stem cell differentiation. By studying oculofacialcardiodental syndrome (OFCD), a rare human genetic disorder characterized by teeth with extremely long roots (radiculomegaly), we unexpectedly discovered that the transcription co-repressor BCOR (Bcl-6 co-repressor) epigenetically regulates dental stem cell function and differentiation via histone demethylases. In this competing renewal, we hypothesize that histone epigenetic modification plays an important role in the regulation of dental stem cell function and differentiation. To test our hypothesis, we propose three specific aims. In Aim 1, we will explore whether and how BCOR epigenetically represses dental stem cell differentiation by histone modification. In Aim 2, we will determine whether and how BCOR mutation epigenetically de-represses gene transcription and thereby promotes dental stem cell differentiation. These two aims will augment our current work and further define how BCOR mutation promotes dental stem cell differentiation in a pathological condition. In Aim 3, we will explore whether and how a newly identified histone demethylase JMJD3 (JmjC domain-containing 3) promotes gene expression and controls dental stem cell differentiation in healthy conditions. By studying both normal and abnormal dental stem cells, our results may provide new insights into the molecular biology of human dental stem cells. Moreover, as demethylases, being enzymes, can be readily targeted by small molecule inhibitors, our work may help to develop novel strategies for promoting dental and craniofacial tissue regeneration and repair.